LANCET: Ovarian teratoma and autoimmune encephalitis

Lancet Neurol. Author manuscript; available in PMC 2009 December 1.

Published in final edited form as:

Lancet Neurol. 2008 December; 7(12): 1091–1098.

Published online 2008 October 11. doi: 10.1016/S1474-4422(08)70224-2 PMCID: PMC2607118

NIHMSID: NIHMS74544

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Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies

Josep Dalmau, Amy J Gleichman,* Ethan G Hughes,* Jeffrey E Rossi, Xiaoyu Peng, Meizan Lai, Scott K Dessain, Myrna R Rosenfeld, Rita Balice-Gordon, and David R Lynch

Department of Neurology (J Dalmau MD, J E Rossi BA, M Lai MD, M R Rosenfeld MD, D R Lynch MD) and Department of Neuroscience (A J Gleichman BS, E G Hughes BS, X Peng BS, R Balice-Gordon PhD), University of Pennsylvania, Philadelphia, PA, USA; Lankenau Institute for Medical Research, Wynnewood, PA, USA (S K Dessain MD); Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA (D R Lynch)

Correspondence to: Josep Dalmau, Division of Neuro-Oncology, Department of Neurology, 3 W Gates, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA, Email: josep.dalmau@uphs.upenn.edu

*These authors contributed equally to this paper

The publisher's final edited version of this article is available at Lancet Neurol

A severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures.

Methods

We describe the clinical characteristics of 100 patients with encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters.

Findings

Median age of patients was 23 years (range 5–76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0.004) and fewer neurological relapses (p=0.009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients’ antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal.

Interpretation

A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies.


NMDA receptors are ligand-gated cation channels with crucial roles in synaptic transmission and plasticity. The receptors are heteromers of NR1 subunits that bind glycine and NR2 (A, B, C, or D) subunits that bind glutamate.1 NR1 and NR2 combine to form receptor subtypes with distinct pharmacological properties, localisation, and ability to interact with intracellular messengers. Overactivity of NMDA receptors causing excitotoxicity is a proposed underlying mechanism for epilepsy, dementia, and stroke, whereas low activity produces symptoms of schizophrenia.2–4We recently identified a disorder, designated anti-NMDA-receptor encephalitis, that associates with antibodies against NR1–NR2 heteromers and results in a characteristic neuropsychiatric syndrome.5 The first patients identified were young women with ovarian teratoma who presented with psychosis or memory problems, rapidly progressing to multiple neurological deficits requiring prolonged intensive care support. Despite the severity of the disorder, patients often recovered after tumour removal and immunotherapy, suggesting an immune-mediated pathogenesis. Preliminary studies suggested the target epitopes were located in extracellular regions of NR1–NR2B NMDA receptors.5 However, selective disruption of receptors containing NR2B, which are predominantly expressed in the forebrain and hippocampus, would not explain the extensive deficits of patients. We postulated that the crucial epitopes were present in the more widely expressed NR1 subunit. If the antibodies were pathogenic we reasoned that their effects on NMDA receptors would be reversible because most patients recover.We report the clinical features of 100 patients, analysing the frequency and type of tumour association, antibody titres, and response to treatment. We also investigate the epitopic region of the NMDA receptor and how antibodies affect NMDA receptors in primary cultures of hippocampal neurons.

ISMH: TESTOSTERONE & CARDIOVASCULAR DISEASE

Testosterone Deficiency as a Risk Factor for Cardiovascular Disease

September 26, 2011

Male gender, diabetes mellitus, and obesity, are known risk factors for the development of cardiovascular disease. Increasing attention has been given in recent years to the link between testosterone deficiency and increased risk of cardiometabolic disease. Recent meta-analyses have demonstrated a correlation between metabolic syndrome (e.g., commonly defined as obesity, diabetes/insulin resistance, hypertension, dyslipoproteinemia and gout) and lower serum testosterone levels.



Hypogonadotropic hypogonadism occurs in up to 33% of men with type 2 diabetes. The Massachusetts Male Aging Study found that low levels of testosterone and sex hormone binding globulin (SHBG) are independent risk factors for the development of type 2 diabetes. In addition, this study demonstrated that low serum testosterone predicts the development of metabolic syndrome.



Declining serum testosterone levels throughout a man’s life are associated with an increase in all-cause mortality and an increase in atherosclerosis, visceral obesity, insulin resistance, dyslipidemia, and hypertension, the key components of the metabolic syndrome. Prospective clinical trials in men with prostate cancer who have undergone androgen deprivation therapy have found increased cardiovascular risk by increasing body weight, reducing insulin sensitivity, and/or resulting in dyslipidemia.



Reference: Ullah MI, Washington T, Kazi M, et al. Testosterone deficiency as a risk factor for cardiovascular disease. Horm Met Res 2001;43:153-164.